Although many men with advanced prostate cancer initially respond to androgen ablation therapy, the development of castration resistance is nearly inevitable. Progression to castration resistance leads to disease progression and, ultimately, death from prostate cancer. Despite intensive efforts, the genetic basis for castration resistance remains incompletely characterized. Similarly, the identification of genetic features that distinguish indolent from lethal disease has proved elusive. Advances in systematic genomic and functional technologies in recent years provide an unprecedented opportunity to make new scientific inroads into these longstanding challenges. The overarching goal of this research is to leverage these advances to address two cardinal questions in prostate cancer research: 1, the genetic determinants of indolent versus aggressive disease; and 2, a systematic understanding of mechanisms of resistance to castration-based therapy. These issues will be addressed through a series of complementary approaches. First, whole genome sequencing will be performed on >80 specimens obtained from castration-resistant bone metastases, or from primary tumors resected following neoadjuvant androgen blockade. Here, the goal is to identify recurrent genomic alterations that are preferentially associated with castration resistance. Next, we will develop a targeted massively parallel sequencing approach to enable high-throughput mutational profiling of mutations and rearrangements characteristic of clinically aggressive and/or castration resistant prostate cancer. This approach will be applied to 300 prostate tumor DNAs, thus providing a robust cohort in which to validate the observations from the whole genome sequencing efforts. The targeted approach may also provide a basis for new diagnostic modalities capable of stratifying prostate cancer patients for genomics-driven clinical trials. In addition, we will perform a genome-scale ORF screen to identify mechanisms of resistance to androgen ablation. Together, these studies should provide many new insights that propel new diagnostic and therapeutic options for men with clinically aggressive and castration-resistant prostate cancer.